HIGH RESOLUTION STUDIES OF THE LARGE RIBOSOMAL SUBUNIT BOUND TO NEWLY DESIGNED I

与新设计的 I 结合的大核糖体亚基的高分辨率研究

• 批准号: 8170648
• 负责人: Joseph Ippolito
• 金额: $ 0.59万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170648
• 关键词: Address; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics; Binding; Chemicals; Clinical; Collimator; Complex; Computer Retrieval of Information on Scientific Projects Database; Development; Funding; Goals; Gram-Positive Bacteria; Grant; Haloarcula marismortui; Infection; Institution; Medical; Pharmacologic Substance; Process; Property; Research; Research Personnel; Resistance; Resolution; Resources; Ribosomes; Source; Structure; Synchrotrons; United States National Institutes of Health; bacterial resistance; base; beamline; cell dimension; design; detector; drug discovery; inhibitor/antagonist; novel; rib bone structure; small molecule

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rib-X Pharmaceuticals, Inc. is a small molecule drug discovery and development company whose goal is to address the medical difficulties presented by increasing bacterial resistance against current antibacterial agents by developing novel chemical classes of anti-infective molecules that target the ribosome. In order to shorten the drug discovery process, we employ a structure-based design strategy that utilizes high resolution crystal structures of the 50S ribosome from the archaeal Haloarcula marismortui, complexed with small molecule inhibitors. Importantly, our research has already led to the identification of multiple clinical candidates with novel antibiotic properties for treating resistant infections. To augment our continuing drug discovery efforts, we have recently crystallized and determined the high resolution structure of the 50S ribosomal subunit from a Gram-positive bacterium. This allows us to target 50S regions not conserved between archeal and eubacterial kingdoms. Given the very large unit cell dimensions of our archeal and eubacterial 50S crystals, we are constrained to use not only a high intensity synchrotron source for x-rays, but also the best beamlines in terms of brightness, beam collimation and detector size, such as those found at NSLS.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 Rib-X Pharmaceuticals，Inc。是一家小分子药物发现和开发公司，其目标是通过开发针对核糖体的抗细菌抗菌药物来解决对当前抗菌剂的细菌耐药性来解决对当前抗菌剂的耐药性。 为了缩短药物发现过程，我们采用了一种基于结构的设计策略，该策略利用了从古细菌卤代菌Marismortui中使用50S核糖体的高分辨率晶体结构，并与小分子抑制剂复杂化。 重要的是，我们的研究已经导致鉴定出具有新型抗生素特性的多个临床候选者，以治疗抗性感染。 为了增加我们持续的药物发现工作，我们最近从革兰氏阳性细菌中结晶并确定了50S核糖体亚基的高分辨率结构。 这使我们能够针对不保守的50年代区域和大细菌王国。 鉴于我们的Archeal和Eubacterial 50S晶体的非常大的单位细胞尺寸，我们被限制在不仅使用X射线的高强度同步加速器源，而且在亮度，光束准确性和检测器尺寸方面也是最佳的光束线，例如在NSLS中发现的梁。